JP2017206552A - NOVEL USE OF IL-1β COMPOUNDS - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide novel use of IL-1β-ligand/IL-1 receptor disrupting compounds in the treatment and/or prevention of auto-inflammatory syndromes.SOLUTION: The invention discloses novel use of IL-1β-ligand/IL-1 receptor disrupting compounds in the treatment and/or prevention of auto-inflammatory syndromes.SELECTED DRAWING: None

Description

The present invention relates to IL-1β-ligand / IL-1 receptor disrupting compounds (herein “IL-β” in the treatment and / or prevention of autoinflammatory syndromes such as juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome. For example, small molecule compounds, IL-1β antibodies or ILs that disrupt IL-1β ligand-IL-1 receptor interaction
-1 receptor antibodies, eg, IL-1β binding molecules disclosed herein, eg, antibodies disclosed herein, eg, IL-1β binding compounds or IL-1 receptor binding compounds, and / or IL Treatment of RNA compounds that reduce either -1β ligand or IL-1 receptor protein levels, and autoinflammatory syndromes in mammals, particularly humans, such as juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome and It relates to a method for preventing.

Interleukin-1β (IL-1beta or IL-1β or interleukin-
1β has the same meaning herein) is a potent immune vehicle that mediates a wide range of immune and inflammatory responses. Inappropriate or excessive IL-1β production can cause various diseases such as sepsis, septic or endotoxic shock, allergies, asthma, bone defects, ischemia, stroke, rheumatoid arthritis and other inflammatory disorders. And related to the pathology of the disorder. Antibodies against IL-1β have been proposed for use in the treatment of IL-1 mediated diseases and disorders; for example, discussion in WO 95/01997 and its introduction and WO 02/16436
(These contents are included by explicit reference.)

Surprisingly, according to the present invention, the IL-1β compound is now a patient, eg, a mammal,
It has been found to be particularly useful for the prevention and treatment of human autoinflammatory syndromes. Autoinflammatory syndromes according to the present invention include, but are not limited to, high titer autoantibodies or antigen-specific T
A group of genetic diseases characterized by recurrent inflammation for cell-deficient autoimmune diseases. Furthermore, the autoinflammatory syndrome according to the present invention shows an increase in IL-1β secretion (loss of the negative regulatory role of pilin which is thought to be mutated in the disease), impaired NFkB activation and leukocyte apoptosis) . The autoinflammatory syndrome according to the present invention is Macklewells syndrome (M
WS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset systemic inflammatory disease (NOMI)
D), certain forms of idiopathic arthritis such as chronic childhood neurocutaneous arthropathy (CINCA) syndrome, familial Mediterranean fever (FMF) and / or systemic onset juvenile idiopathic arthritis (SOIJA), systemic onset idiopathic A particular form of juvenile rheumatoid arthritis, such as juvenile rheumatoid arthritis, and / or a particular form of adult rheumatoid arthritis. Preferably, IL-1β compounds are useful in the prevention and treatment of juvenile rheumatoid arthritis and adult rheumatoid arthritis and / or McKellwells syndrome.

  In accordance with certain discoveries of the invention, the following embodiments are provided:

The present invention relates to compositions and methods for preventing and treating autoinflammatory syndromes in mammals, including humans. Thus, IL-1β compounds are also useful for producing medicaments and medicaments for treating autoinflammatory syndromes. In certain aspects, such medicaments and agents comprise a therapeutically effective amount of an IL-1β compound together with a pharmaceutically acceptable carrier.

In a further aspect, the present invention specifically relates to any of the above or below polypeptides in the prevention and / or treatment of juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome and / or other autoinflammatory syndromes and / or McKlwells syndrome, For example, I
There is provided the use of an antibody that binds to an L-1β ligand or IL-1β receptor, preferably an IL-1β ligand. Optionally, the antibody is a monoclonal antibody, a humanized antibody, an antibody fragment or a single chain antibody. In certain aspects, the present invention relates to an isolated antibody that binds to an IL-1β ligand. In other aspects, the antibody inhibits or neutralizes the activity of IL-1β ligand (antagonist antibody). In other aspects, the antibody is a monoclonal antibody having human or non-human complementarity determining region (CDR) residues and human framework region (FR) residues. The antibody can be labeled and immobilized on a solid support. In a further aspect, the antibody is an antibody fragment, a monoclonal antibody, a single chain antibody, or an anti-idiotype antibody. In yet another aspect, the present invention provides a composition comprising an anti-IL-1β ligand or IL-1β receptor antibody, preferably an anti-IL-1β ligand antibody, together with a pharmaceutically acceptable carrier. In certain aspects, the composition comprises a therapeutically effective amount of the antibody. Preferably, the composition is sterilized. The composition can be administered in the form of a liquid pharmaceutical formulation that can achieve long-term storage. Alternatively, the antibody is a monoclonal antibody, an antibody fragment, a humanized antibody, or a single chain antibody.

In a further aspect, the present invention provides a positive feedback loop of IL-1β in vivo in the prevention and / or treatment of juvenile rheumatoid arthritis or adult rheumatoid arthritis and / or other autoinflammatory syndromes and / or Maccle Wells syndrome. The use of IL-1β compounds, such as IL-1β antibodies, is provided. This positive feedback in vivo induces autonomous overproduction of IL-1β in patients.

In a further aspect, the invention relates to a disease in a disease having a mutation in the MEFV gene located on chromosome 16p13 and encoding the protein pilin (also known as malenostrin).
Use of an L-1β compound, eg, an IL-1β antibody is provided. Pyrin is expressed on granulocytes, monocytes and synovial fibroblasts. Pyrin is involved in IL-1β production.

In a further aspect, the present invention provides: (a) a composition of matter comprising an anti-IL-1β ligand or IL-1β receptor antibody, preferably an anti-IL-1β ligand antibody; (b) a container comprising the composition And (c) said anti-IL-1β ligand, preferably in the use of an anti-IL-1β ligand antibody, in the treatment of juvenile rheumatoid arthritis or adult rheumatoid arthritis and / or other autoinflammatory syndromes and / or Maccle Wells syndrome; Or a label that is attached to the container that mentions the use of an IL-1β receptor antibody, or a product that includes a package insert included in the container. The composition may comprise a therapeutically effective amount of an anti-IL-1β ligand or IL-1β receptor antibody, preferably an anti-IL-1β ligand.

In a further aspect, the present invention provides therapeutically effective amounts of free or salt forms, preferably pharmaceutically acceptable delivery forms of IL-1β compounds and free or salt forms, for example intravenously or subcutaneously. There is provided a method or use as described above comprising co-administration of a second agent that is an inflammatory compound.

In a further embodiment, the IL-1β compound used according to the present invention comprises an IL- comprising an antigen binding site comprising at least one immunoglobulin heavy chain variable domain (V _H ) comprising in turn the hypervariable regions CDR1, CDR2 and CDR3. A 1β-binding molecule comprising the CDR1
Has the amino acid sequence Val-Tyr-Gly-Met-Asn, the CDR2 comprising the amino acid sequence Ile-Ile-Trp-Tyr-Asp-Gly-Asp-Asn-Gln-Ty
r-Tyr-Ala-Asp-Ser-Val-Lys-Gly and the CDR
3 is a binding molecule having the amino acid sequence Asp-Leu-Arg-Thr-Gly-Pro; as well as their direct equivalents.

In a further aspect, the IL-1β compound used in accordance with the present invention comprises IL-1β binding comprising at least one immunoglobulin light chain variable domain (V _L ) comprising in turn the hypervariable regions CDR1 ′, CDR2 ′ and CDR3 ′. The CDR1 ′ is an amino acid sequence Arg-Ala-Ser-Gln-Ser-Ile-Gly-Ser-Ser-Le.
u-His, the CDR2 'is the amino acid sequence Ala-Ser-Gln-Ser-Ph
e-Ser and the CDR3 'is the amino acid sequence His-Gln-Ser-Ser
-A binding molecule with Ser-Leu-Pro as well as its direct equivalent.

In a further aspect, the IL-1β compound used according to the invention is, for example,
For the manufacture of a medicament for treating juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome and / or other autoinflammatory syndromes, preferably juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome and / or Maccle Wells syndrome, Single domain IL-1β comprising an isolated immunoglobulin heavy chain comprising a heavy chain variable region (V _H ) as defined above
It is a binding molecule.

In a further embodiment, the IL-1β compound used in accordance with the present invention is an IL-1β binding molecule comprising both heavy chain (V _H ) and light chain (V _L ) variable domains, wherein said IL-1β
The 1β binding molecule is a) an immunoglobulin heavy chain variable domain (V _H ) that in turn comprises the hypervariable regions CDR1, CDR2 and CDR3, which CDR1 has the amino acid sequence Val-Tyr-Gly-Met.
-Asn, and the CDR2 has the amino acid sequence Ile-Ile-Trp-Tyr-Asp-
Gly-Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-
Lys-Gly and the CDR3 has the amino acid sequence Asp-Leu-Arg-Th
a domain having r-Gly-Pro (V _H ), and b) an immunoglobulin light chain variable domain (V _L ) comprising in turn hypervariable regions CDR1 ′, CDR2 ′ and CDR3 ′, wherein CDR1 ′ is an amino acid Arg-Ala-Ser sequence
-Gln-Ser-Ile-Gly-Ser-Ser-Leu-His
2 ′ has the amino acid sequence Ala-Ser-Gln-Ser-Phe-Ser and the CDR3 ′ has the amino acid sequence Gln-Gln-Arg-Ser-Asn-Trp-Met-
Domain with Phe-Pro (V _L );
Binding molecules comprising at least one antigen binding site comprising: as well as their direct equivalents.

Unless otherwise stated, any polypeptide chain is described herein as having an amino acid sequence beginning at the N-terminus and ending at the C-terminus.
When the antigen binding site contains both _VH and _VL domains, they can be located on the same polypeptide molecule or, preferably, each domain can be on a different chain, but the _VH domains are It is part of an immunoglobulin heavy chain or fragment thereof, and _VL is part of an immunoglobulin light chain or fragment thereof.

An “IL-1β binding molecule” is an IL− molecule either alone or in combination with another molecule.
By any molecule capable of binding to 1β antigen is meant. A binding reaction is a biometric that measures inhibition of binding of IL-1β to its receptor, eg, with reference to a negative control test with an irrelevant specificity but of the same isotype, eg, an anti-CD25 antibody. It can be demonstrated by standard methods (qualitative assays) including assays or any type of binding assay. Advantageously, the binding of the IL-1β binding molecules of the invention to IL-1β can be shown in a competitive binding assay.

Examples of antigen binding molecules include antibodies produced by B cells or hybridomas and chimeric, CDR-grafted or human antibodies or any fragment thereof, such as F
(Ab ′) ₂ and Fab fragments, as well as single chain or single domain antibodies.

Single chain antibodies usually consist of the antibody heavy and light chain variable domains covalently linked by a peptide linker consisting of 10 to 30 amino acids, preferably 15 to 25 amino acids. Thus, such structures do not include heavy and light chain constant portions, and small peptide spacers are believed to be less antigenic than the entire constant portion.
A “chimeric antibody” is one in which the heavy and / or light chain constant regions are derived from human, whereas both the heavy and light chain variable domains are derived from non-human (eg, mouse) or human. By an antibody derived from a different human antibody is meant. A “CDR-grafted antibody” is one in which the hypervariable region (CDR) is derived from a donor antibody, such as a non-human (eg, murine) antibody or a different human antibody, while all or substantially all of the immunoglobulin. Means an antibody in which the constant region and the highly conserved portion of the variable domain, ie, the framework region is derived from the recipient antibody, eg, a human-derived antibody. However, the CDR-grafted antibody may comprise a small number of amino acids of the donor sequence in the framework region, eg, in the portion of the framework region adjacent to the hypervariable region. “Human antibody” means, for example, EP 0546073 B1, USP 554580.
6, USP 5569825, USP 5625126, USP 5633425, US
P 5661016, USP 5770429, EP 0438474 B1 and EP
As described in general terms in 0463151 B1, the constant and variable regions of both heavy and light chains are all human or substantially identical to human-derived sequences, but not necessarily from the same antibody. And includes antibodies produced by mice in which the variable and constant region genes of mouse immunoglobulins have been replaced by their human equivalents.

Particularly preferred IL-1β binding molecules of the invention are human antibodies, especially the examples below and WO
It is the ACZ885 antibody described in 02/16436.

Thus, in a preferred chimeric antibody of the present invention, both heavy and light chain variable domains are derived from humans, for example, those of the ACZ885 antibody shown in SEQ ID NO: 1 and SEQ ID NO: 2. The constant region domain is also preferably, eg, “Sequences of Protein
s of Immunological Interest ”, Kabat EA et al., US Department of Health and H
It contains the appropriate human constant region domains described in uman Services, Public Health Service, National Institute of Health.

The hypervariable region may bind to any kind of framework region, but is preferably derived from human. Suitable framework regions are described in Kabat EA et al., Ibid. A preferred heavy chain framework is a human heavy chain framework, such as that of the ACZ885 antibody shown in SEQ ID NO: 1. It is the sequence FR1, FR2, FR3 and FR4
It consists of the area. Similarly, SEQ ID NO: 2 has the sequence FR1 ′, FR2 ′, FR3 ′ and F
A preferred ACZ885 light chain framework consisting of the region of R4 ′ is shown.

Accordingly, the present invention also provides either a first domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 1 starting from amino acid 1 and ending with amino acid 118, or the first domain described above IL-, comprising at least one antigen-binding site comprising a second domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 2 starting from amino acid 1 and ending with amino acid 107 A 1β binding molecule is provided.

Monoclonal antibodies raised against proteins found naturally in all humans
In non-human systems, eg, in mice, it typically develops and as such is typically a non-human protein. As a direct consequence of this, cross-species antibodies, such as those produced by hybridomas, when administered to humans elicit unwanted immune responses that are preferentially mediated by the constant portions of cross-species immunoglobulins. This clearly limits the use of such antibodies since they cannot be administered over a long period of time. Therefore, when administered to humans, it does not elicit substantial allogeneic reactions, single chain, single domain,
It is particularly preferred to use chimeric, CDR-grafted or especially human antibodies.

In view of the above, further preferred IL-1β binding molecules of the invention are
a) (i) a variable domain comprising in turn the hypervariable regions CDR1, CDR2 and CDR3 and (ii) a constant part of a human heavy chain or a fragment thereof, said CDR1 comprising the amino acid sequence Val-Tyr-Gly-Met-Asn The CDR2 has the amino acid sequence I
le-Ile-Trp-Tyr-Asp-Gly-Asp-Asn-Gln-Tyr-T
a constant part or fragment thereof having yr-Ala-Asp-Ser-Val-Lys-Gly and the CDR3 has the amino acid sequence Asp-Leu-Arg-Thr-Gly-Pro and b) (i) in turn A variable domain comprising these hypervariable regions and optionally also the CDR1 ′, CDR2 ′ and CDR3 ′ hypervariable regions and (ii) a constant part of a human light chain or a fragment thereof, the CDR1 ′ comprising the amino acid sequence Arg − Ala-Ser
-Gln-Ser-Ile-Gly-Ser-Ser-Leu-His
2 ′ has the amino acid sequence Ala-Ser-Gln-Ser-Phe-Ser, and the CDR3 ′ has the amino acid sequence His-Gln-Ser-Ser-Ser-Leu-Pro, or a constant part thereof or a fragment thereof,
A human anti-IL-1β antibody comprising at least: and direct equivalents thereof.

Alternatively, the IL-1β binding molecule of the present invention comprises
a) a first domain comprising in turn the hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence Val-Tyr-Gly-Met-Asn,
2 is the amino acid sequence Ile-Ile-Trp-Tyr-Asp-Gly-Asp-Asn-
A domain having Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly and the CDR3 has the amino acid sequence Asp-Leu-Arg-Thr-Gly-Pro;
b) a second domain comprising the hypervariable regions CDR1 ′, CDR2 ′ and CDR3 ′, said CDR1 ′ comprising the amino acid sequence Arg-Ala-Ser-Gln-Ser-Ile-Gl
y-Ser-Ser-Leu-His, the CDR2 'is the amino acid sequence Ala-Se
r-Gln-Ser-Phe-Ser, and the CDR3 ′ has the amino acid sequence His
A domain having Gln-Ser-Ser-Ser-Leu-Pro, and c) at the N-terminus of the first domain and at the C-terminus of the second domain or at the C-terminus of the first domain and Single chain binding molecules comprising an antigen binding site comprising a peptide linker attached to either at the N-terminus of the two domains; as well as their direct equivalents.

As is well known, minor changes in the amino acid sequence, such as single, few or even a few amino acid deletions, additions or substitutions, are allelic forms of the original protein having substantially identical properties. Will lead to.

Therefore, the term “their direct equivalents” is
(I) The hypervariable regions CDR1, CDR2 and CDR3 taken as a whole are at least 80% homologous to the hypervariable regions shown above, preferably at least 90% homologous, more preferably at least 95% homologous; And (ii) substantially the same extent of IL-1β as the reference molecule having the same framework region as that of molecule X but having the same hypervariable regions CDR1, CDR2 and CDR3 as shown above. All single domain IL- capable of inhibiting binding to its receptor
1β-binding molecule (molecule X),
Or (i) the hypervariable regions CDR1, CDR2, CDR3, CDR1 ′, CDR taken as a whole
2 ′ and CDR3 ′ are at least 80% homologous to the hypervariable region shown above, preferably at least 90% homologous, more preferably at least 95% homologous, and (ii) identical to molecule X ′ IL-1β with a framework region and a constant portion, but with the same hypervariable regions CDR1, CDR2, CDR3, CDR1 ′, CDR2 ′ and CDR3 ′ as shown above to substantially the same extent as the reference molecule All IL- with at least two domains per binding site that are capable of inhibiting the binding of to the receptor
1β-binding molecule (molecule X ′).

In a further aspect, the present invention also provides an IL-1β binding molecule comprising both heavy chain (V _H ) and light chain (V _L ) variable domains, wherein the IL-1β binding molecule is a) hypervariable in order. An immunoglobulin heavy chain variable domain (V _H ) comprising the regions CDR1, CDR2 and CDR3, the CDR1 comprising the amino acid sequence Ser-Tyr-Trp-Ile
-Gly, and the CDR2 has the amino acid sequence Ile-Ile-Tyr-Pro-Ser-
Asp-Ser-Asp-Thr-Arg-Tyr-Ser-Pro-Ser-Phe-
Gln-Gly and the CDR3 has the amino acid sequence Tyr-Thr-Asn-Tr
a domain with p-Asp-Ala-Phe-Asp-Ile (V _H ), and b) amino acid sequence Gln-Gln-Arg-Ser-Asn-Trp-Met-Phe-
An immunoglobulin light chain variable domain (V _L ) comprising a hypervariable region CDR3 ′ with Pro;
Binding molecules comprising at least one antigen binding site comprising: as well as their direct equivalents are provided.

In a further aspect, the invention provides an IL-1β binding molecule comprising both heavy chain (V _H ) and light chain (V _L ) variable domains, the IL-1β binding molecule comprising:
a) an immunoglobulin heavy chain variable domain (V _H ) comprising in turn the hypervariable regions CDR1, CDR2 and CDR3, said CDR1 comprising the amino acid sequence Ser-Tyr-Trp-Ile
-Gly, and the CDR2 has the amino acid sequence Ile-Ile-Tyr-Pro-Ser-
Asp-Ser-Asp-Thr-Arg-Tyr-Ser-Pro-Ser-Phe-
Gln-Gly and the CDR3 has the amino acid sequence Tyr-Thr-Asn-Tr
a domain (V _H ) having p-Asp-Ala-Phe-Asp-Ile, and b) an immunoglobulin light chain variable domain (V _L ) comprising in turn the hypervariable regions CDR1 ′, CDR2 ′ and CDR3 ′ The CDR1 ′ has the amino acid sequence Arg-Ala-Ser
-Gln-Ser-Val-Ser-Ser-Tyr-Leu-Ala, the CDR
2 ′ has the amino acid sequence Asp-Ala-Ser-Asn-Arg-Ala-Thr;
The CDR3 ′ has the amino acid sequence Gln-Gln-Arg-Ser-Asn-Trp-
Provided are binding molecules comprising at least one antigen binding site comprising a domain (V _L ) having Met-Phe-Pro; and direct equivalents thereof.

As used herein, amino acid sequences are at least 80% homologous to each other, in which case they are optimally aligned and no gaps or insertions in the amino acid sequence are non-
When calculated as the same residue, it has at least 80% of the same amino acid residues in similar places.

Inhibition of binding of IL-1β to its receptor can be conveniently tested in a variety of assays, including assays such as those described in WO 02/16436. “Same degree”
The term means that the reference and equivalent molecules exhibit essentially identical IL-1β binding inhibition curves in one of the above assays on a statistical basis. For example, the IL-
IC ₅₀ that 1β-binding molecules typically have for inhibiting the binding of IL-1β to its receptor
The value is preferably within ± 5 of the IC ₅₀ of the corresponding reference molecule, preferably substantially the same when assayed as described above.

For example, the assay used may be an assay for competitive inhibition of binding of IL-1β by soluble IL-1β receptors and IL-1β binding molecules of the invention.

Most preferably, the human IL-1β antibody used according to the invention is
a) a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 1 beginning at amino acid 1 and ending with amino acid 118, and one heavy chain comprising a constant portion of a human heavy chain; and b At least a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 2 starting from amino acid 1 and ending with amino acid 107, as well as one light chain comprising the constant part of a human light chain Human IL-1 antibody.

More preferably, the IL-1β binding molecule for use in accordance with the present invention is ACZ88.
5 (see Examples).

The constant part of the human heavy chain may be γ ₁ , γ ₂ , γ ₃ , γ ₄ , μ, α ₁ , α ₂ , δ or ε type, preferably γ type, more preferably γ ₁ type, On the one hand, the constant part of the human light chain may be κ or λ type (including λ ₁ , λ ₂ and λ ₃ subtypes), but is preferably the κ type. The amino acid sequences of all these constant parts are Kaba
t et al., given in the same book.

The IL-1β binding molecule of the present invention is produced, for example, by recombinant DNA technology as described in WO 02/16436.

In another embodiment of the invention, the IL-1β compound comprises Glu 64 residue of mature human IL-1β (Glu 64 residue of mature human IL-1β corresponds to residue 180 of the human IL-1β precursor). It may be an antibody having binding specificity for an antigenic epitope of human IL-1β comprising a loop comprising. It is most surprising that this epitope is outside the recognition site of the IL-1β receptor, and thus antibodies of this epitope, such as the ACZ885 antibody, have the ability to inhibit the binding of IL-1β to its receptor It is. Thus, the use of such antibodies to treat juvenile rheumatoid arthritis and adult rheumatoid arthritis and / or autoinflammatory syndrome and / or McKell Wells syndrome is novel and within the scope of the present invention.

Accordingly, in a further aspect, the present invention comprises the Glu 64 residue of mature human IL-1β for treating juvenile or adult rheumatoid arthritis and / or autoinflammatory syndrome and / or Maccle Wells syndrome Human IL-1 containing loop
including the use of antibodies to IL-1β that have antigen binding specificity for the antigenic epitope of β and that can inhibit the binding of IL-1β to its receptor.

In a further aspect, the present invention provides:
i) Glu 6 for preventing and / or treating juvenile rheumatoid arthritis or adult rheumatoid arthritis and / or autoinflammatory syndrome and / or Maccle Wells syndrome
Use of an antibody against IL-1β having antigen binding specificity for an antigenic epitope of mature human IL-1β comprising a loop comprising 4 and having the ability to inhibit binding of IL-1β to its receptor;
ii) IL having antigen binding specificity for an antigenic epitope of mature human IL-1β comprising a loop comprising Glu 64 and having the ability to inhibit binding of IL-1β to its receptor
A method for preventing and / or treating juvenile rheumatoid arthritis or adult rheumatoid arthritis and / or autoinflammatory syndrome and / or Maccle Wells syndrome, comprising administering to the patient an effective amount of an antibody against -1β ,
iii) an antigen against an antigenic epitope of mature human IL-1β comprising a loop comprising Glu 64 for treating juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome and / or autoinflammatory syndrome and / or McKlwells syndrome A pharmaceutical composition comprising an antibody against IL-1β having binding specificity and the ability to inhibit binding of IL-1β to its receptor, together with a pharmaceutically acceptable excipient, diluent or carrier object,
iv) for the manufacture of a medicament for treating juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome and / or autoinflammatory syndrome and / or Maccle Wells syndrome,
IL-1β having antigen binding specificity for an antigenic epitope of mature human IL-1β comprising a loop containing Glu 64 and having the ability to inhibit binding of IL-1β to its receptor
Use of antibodies against.

For purposes of this description, the antibody has the ability to inhibit binding of IL-1β to its receptor to substantially the same extent as the ACZ885 antibody, ie, for example, the standard BI described in the Examples
Measured by Acore analysis, 10 nM or less, eg 1 nM or less,
An antibody is “capable of inhibiting IL-1β binding” when it has an equilibrium dissociation constant (K _D ) of preferably 100 pM or less, more preferably 50 pM or less.

Thus, in a further aspect, the present invention relates to binding to IL-1β for treating juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome and / or autoinflammatory syndrome, more preferably about 10 nM, 1 nM, more preferably 100 pM. preferably provides the use of antibodies with 50pM or less K _D. This aspect of the invention also provides for Glu 6
I having binding specificity for an antigenic determinant of mature human IL-1β comprising a loop containing 4
Thus, uses, methods and compositions for such high affinity antibodies are included as described above for antibodies to L-1β.

In this description, the term “juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome and / or autoinflammatory syndrome” refers to a disease or medical condition that includes causal, development, advancement, survival or pathology of the disease or condition. Includes all diseases and medical conditions in which juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome and / or autoinflammatory syndrome play a role, whether direct or indirect.

In this description, the term “Mccle Wells Syndrome” (also “MWS”), whether directly or indirectly in a disease or medical condition, including causal, development, advancement, survival or pathology of the disease or condition, Where “Muckle Wells Syndrome” plays a role
Includes all diseases and medical conditions.

The compounds of formula I can be used as active ingredients alone or as other agents, eg as adjuvants, eg for the treatment or prevention of allogeneic or xenogeneic, acute or chronic rejection or inflammatory or autoimmune diseases, eg Can be administered together with immunosuppressive or immunomodulatory agents or other anti-inflammatory agents, or chemotherapeutic agents such as anti-proliferative agents of malignant cells. For example,
The antibodies of the present invention may be calcineurin inhibitors such as cyclosporin A or FK506.
MTOR inhibitors such as rapamycin, 40-O- (2-hydroxyethyl) -rapamycin, CCI779, ABT578, AP23573, AP23464, AP236;
75, AP23841, TAFA-93, biolimus-7 or biolimus-9; ascomycin with immunosuppressive properties, such as ABT-281, ASM981, etc .; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; Mycophenolic acid or salt; mycophenolate mofetil; 15-deoxyspergualin or immunosuppressive homologues, analogs or derivatives thereof; PKC inhibitors such as described in WO 02/38561 or WO 03/82859 Such as the compound of Example 56 or 70; a JAK3 kinase inhibitor such as N-
Benzyl-3,4-dihydroxy-benzylidene-cyanoacetamide □ -cyano- (3
, 4-dihydroxy)-] N-benzylcinnamamide (tyrphostin AG490), prodigiosin 25-C (PNU156804), [4- (4′-hydroxyphenyl)-
Amino-6,7-dimethoxyquinazoline] (WHI-P131), [4- (3′-bromo-4′-hydroxylphenyl) -amino-6,7-dimethoxyquinazoline] (WHI—
P154), [4- (3 ′, 5′-dibromo-4′-hydroxylphenyl) -amino-
6,7-dimethoxyquinazoline] WHI-P97, KRX-211, in free or pharmaceutically acceptable salt form, for example 3-{(3R, 4R) -4-methyl-3-
[Methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo-propionitrile (also referred to as CP-690,550)
Or a compound as described in WO 04/052359 or WO 05/066156; an immunosuppressive monoclonal antibody, eg a monoclonal antibody against leukocyte receptors, eg MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28
, CD40, CD45, CD52, CD58, CD80, CD86 or ligands thereof; other immunomodulatory compounds, eg, having at least the extracellular portion of CTLA4 or variants thereof, eg, binding to non-CTLA4 protein sequences A recombinant binding molecule having at least the extracellular domain portion of CTLA4 or a variant thereof, eg C
TLA4Ig (eg, designated as ATCC 68629) or variants thereof, eg, LEA29Y; adhesion molecule inhibitors, eg, LFA-1 antagonist, ICAM-1
Or a -3 antagonist, a VCAM-4 antagonist or a VLA-4 antagonist; or a chemotherapeutic agent such as paclitaxel, gemcitabine, cisplastin, doxorubicin or 5-fluorouracil; or an anti-infective agent. Immunomodulators that are likely to be useful in combination with the compounds of the present invention include, for example:

で示されるラパマイシンおよびラパマイシン誘導体、例えば
４０−Ｏ−アルキル−ラパマイシン誘導体、例えば、４０−Ｏ−ヒドロキシアルキル−ラ
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バロリムス）、
３２−デオキソ−ラパマイシン誘導体および３２−ヒドロキシ−ラパマイシン誘導体、例
えば、３２−デオキソラパマイシン、
１６−Ｏ−置換ラパマイシン誘導体、例えば、１６−ペンタ−２−イニルオキシ−３２−
デオキソラパマイシン、１６−ペンタ−２−イニルオキシ−３２（ＳまたはＲ）−ジヒド
ロ−ラパマイシン、１６−ペンタ−２−イニルオキシ−３２（ＳまたはＲ）−ジヒドロ−
４０−Ｏ−（２−ヒドロキシエチル）−ラパマイシン、
酸素基で４０位をアシル化されているラパマイシン誘導体、例えば、４０−［３−ヒドロ
キシ−２−（ヒドロキシ−メチル）−２−プロピオン酸メチル］−ラパマイシン（ＣＣＩ
７７９としても既知）、
４０位をヘテロシクリルにより置換されているラパマイシン誘導体、例えば、４０−エピ
−（テトラゾリル）−ラパマイシン（ＡＢＴ５７８としても既知）、
いわゆる、例えば、ＷＯ９８０２４４１、ＷＯ０１１４３８７およびＷＯ０３６４３８３
に記載されているようなラパログ、例えば、ＡＰ２３５７３および
ＴＡＦＡ−９３、ＡＰ２３４６４、ＡＰ２３６７５、ＡＰ２３８４１およびバイオリムス
の名の下に記載されている化合物（例えば、バイオリムスＡ９）
ＴＡＦＡ−９３およびバイオリムス（バイオリムスＡ９）の名の下に記載されている化合
物を含む。 A mediator of mTOR activity, eg an inhibitor, eg a formula

A rapamycin and a rapamycin derivative, such as a 40-O-alkyl-rapamycin derivative, such as a 40-O-hydroxyalkyl-rapamycin derivative, such as 40-O- (2-hydroxy) -ethyl-rapamycin (everolimus),
32-deoxo-rapamycin derivatives and 32-hydroxy-rapamycin derivatives, such as 32-deoxorapamycin,
16-O-substituted rapamycin derivatives such as 16-pent-2-ynyloxy-32-
Deoxorapamycin, 16-pent-2-ynyloxy-32 (S or R) -dihydro-rapamycin, 16-pent-2-ynyloxy-32 (S or R) -dihydro-
40-O- (2-hydroxyethyl) -rapamycin,
Rapamycin derivatives acylated at position 40 with an oxygen group, for example, 40- [methyl 3-hydroxy-2- (hydroxy-methyl) -2-propionate] -rapamycin (CCI
779)
A rapamycin derivative substituted at position 40 by heterocyclyl, such as 40-epi- (tetrazolyl) -rapamycin (also known as ABT578),
So-called, for example, WO9802441, WO0114387 and WO0364383
Rapalogs as described in e.g. AP23573 and TAFA-93, AP23464, AP23675, AP23841 and the compounds described under the name biolimus (e.g. biolimus A9)
Includes compounds described under the names TAFA-93 and Biolimus (Biolimus A9).

In this description, the term “treatment” or “treating” refers to the risk of having a disease or a patient suspected of having a disease as well as being diagnosed as being ill or having a disease or condition. Means both preventive or preventive treatment, as well as curative or palliative treatment, including the treatment of patients and the suppression of clinical relapse. Effective treatment of the present invention includes alleviating all recoverable symptoms, but not alleviating all unrecoverable symptoms. For example, one of the symptoms of Maccle Wells is progressive neurological hearing loss that usually cannot be resolved and therefore does not expect this symptom to be treated. However, other recoverable symptoms of Maccle Wells,
For example, skin tumors, muscle pain, fever, fatigue and conjunctivitis can be completely absent with the effective treatment of the present invention. Other measures of effective treatment include a reduction in biomarkers associated with autoinflammatory syndromes, eg, McKell Wells, ie the normal range of patients, ie <10 mg /
Serum amyloid protein (SAA) and c-reactive protein (CRP) from L serum
).

In the present description, the disease “Mccle Wells” refers to clinical (molecular pathology) arthritis and urticaria, acute febrile inflammation manifestations of progressive neurological hearing loss and optionally long-term multi-organ amyloidosis (about 25% in this case) Measured for symptoms. Molecular pathology is chromosome 16
It is caused by one or more mutations in the MEFV gene located at p13 and encoding a protein called pilin.

An IL-1β binding molecule as defined above, in particular the IL-1β binding molecule of the first and second aspects of the invention, an antibody having specific binding to an antigenic epitope of mature human IL-1β comprising a loop comprising Glu64, In particular an antibody capable of inhibiting the binding of IL-1β to the receptor;
And from about 10 nM, 1 nM, referred preferably 100 pM, more preferably antibodies against IL-l [beta] having a _{K D} for binding to 50pM or less IL-l [beta] and the antibodies of the present invention herein.

In a further aspect of the invention, further uses of IL-1β compounds, eg, antibodies of the invention, are as follows:
Inflammatory bowel disease (IBD), juvenile arthritis, reactive arthritis, ankylosing spondylitis, coronary syndrome, arterial restenosis, cystic fibrosis, Alzheimer's disease, multiple myeloma, arteriosclerosis, pulmonary fibrosis, muckle Prevention and treatment of Wells and chronic obstructive pulmonary disease (COPD).

For all indications described herein (application of the invention), the appropriate dose will, of course, be the specific IL-1β compound used, eg the antibody of the invention, the host, the route of administration and the treatment. It depends on the nature and severity of the condition. However, in prophylactic use, satisfactory results are generally indicated to be obtained at dosages of from about 0.05 mg to about 10 mg per kilogram body weight, more usually from about 0.1 mg to about 5 mg per kilogram body weight. ing. The antibodies of the invention are conveniently administered parenterally, intravenously, eg, in the antecubital or other peripheral vein, intramuscularly, or subcutaneously.

In another aspect, the invention relates to the surprising frequency of administration for therapeutic use, ie the schedule of treatment with an IL-1β compound, preferably an IL-1β antibody, more preferably ACZ885 (typical dose, patient's Per kilogram of body weight, for example, from about 0.1 mg to about 50 mg, more preferably from 0.5 mg to 20 mg, even more preferably from 1 mg to 10 mg ACZ885), at a frequency of once or less per week, more preferably every 2 weeks Frequency of once or less, more preferably once or less than 3 weeks, more preferably once or less than once a month, more preferably once or less than February Preferably once in March or less frequently, even more preferably once in April or less frequently, even better More preferably, it may be a frequency of once or less than 5 months, or even more preferably a frequency of once or less than 6 months. Most preferably once a month.

The pharmaceutical compositions of the invention can be manufactured in a conventional manner. The composition according to the invention is preferably provided in a lyophilized dosage form. For direct administration it is dissolved in a suitable aqueous carrier, for example sterile water for injection or sterile buffered saline. When it is desired to make a larger volume solution for administration by infusion rather than as a bolus injection, it is advantageous to incorporate human serum albumin or the patient's own heparinized blood into saline at the time of formulation. The excessive presence of such physiologically inert proteins prevents loss of antibodies due to adsorption onto the walls of the containers and tubes used in the infusion. If albumin is used, a suitable concentration is 0.5-4.5% by weight of saline.

  The invention is further illustrated by way of example in the following examples.

ＡＣＺ８８５ 軽鎖可変領域 配列番号２

Example
Example 1: ACZ885
The structure and fabrication of ACZ885 is described, for example, in WO 02/16436. Briefly, the amino terminal sequences of the heavy and light chain variable regions and the corresponding DNA sequences are CD
R is given in SEQ ID NO: 1 and SEQ ID NO: 2, shown in italics and underlined letters.
ACZ885 heavy chain variable region SEQ ID NO: 1

ACZ885 light chain variable region SEQ ID NO: 2

Example 2: Biochemical and biological data of ACZ885 The monoclonal antibody ACZ885 has been found to neutralize the activity of interleukin-1β in vitro. In addition, monoclonal antibodies are characterized for binding to recombinant human IL-1β by surface plasmon resonance analysis. The mode of neutralization is assessed by competitive binding studies with soluble IL-1 receptor. The biological activity of antibody ACZ885 against recombinant and naturally occurring IL-1β is measured in primary human cells in response to stimulation by IL-1β.

結論：ＡＣＺ８８５は、極めて高い親和性で組換えヒトＩＬ−１ベータに結合する。 Measurement of equilibrium dissociation constants Association and dissociation rate constants for the binding of recombinant human IL-1 beta to ACZ885 are determined by surface plasmon resonance analysis. Immobilize ACZ885 and 1 to 4
Recombinant IL-1β binding in the nM concentration range is measured by surface plasmon resonance.
The format chosen represents a monovalent interaction, thus allowing the binding event of IL-1β to ACZ885 to be handled according to 1: 1 stoichiometry. Data analysis is performed using BIAevaluation software.

Conclusion: ACZ885 binds to recombinant human IL-1 beta with very high affinity.

Example 3: Clinical trial of ACZ885 To assess the suitability of IL-1β compounds, such as ACZ885, for example, NALP3
Open-label, single center, dose escalation of ACZ885 (human anti-IL-1β monoclonal antibody) to assess clinical efficacy, safety, pharmacokinetics and pharmacodynamics in patients with MW syndrome, characterized by mutations Conduct the test.
Patients are treated with a single dose infusion of ACZ885 (10 mg / kg iv). Clinical response by improving symptoms (eg skin tumors, myalgia, fever, fatigue), and acute phase proteins, serum amyloid protein (SAA) and c-reactive protein (CRP)
) To determine In addition, treatment response is assessed by analysis of mRNA obtained from peripheral blood cells. A second treatment (1 mg / kg iv) is performed after recurrence of clinical symptoms.

Results: Clinical remission of symptoms (fever, tumor, conjunctivitis) within 3 days, and normal range of patients (
Reduction of CRP and SAA to <10 mg / L). Clinical remission of symptoms at the first infusion at least 134 days, typically 160-200 days. With a second treatment at a low dose, the patient responds with improved symptoms and normalization of acute phase protein.

Analysis of mRNA obtained from peripheral blood cells demonstrates down-regulation of IL-1b and IL-1b-induced gene transcription within 24 hours of treatment with ACZ885. This is ACZ8
This suggests that 85 can interrupt the positive feedback loop in vivo that leads to autonomous overproduction of IL-1β in patients. This assertion is also supported by the initial properties of the PZ / PD effect of ACZ885, which shows an interference with IL-1b production following treatment of the patient with ACZ885. This particular ability of ACZ885 can contribute to long-term clinical effects (indicating a causal relationship).

In a further embodiment, the IL-1β compound used in accordance with the present invention is an IL-1β binding molecule comprising both heavy chain (V _H ) and light chain (V _L ) variable domains, said IL-1β binding molecule A) an immunoglobulin heavy chain variable domain (V _H ) comprising in turn the hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence Val-Tyr-Gly-Met-Asn, The amino acid sequence Ile-Ile-Trp-Tyr-Asp-Gly-Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly has the amino acid sequence Asp-Leu-Arg -Domain with Thr-Gly-Pro (V _H ), and b) hypervariable region CDR1 ′, CDR2 ′ in turn And a CDR3 ′ comprising an immunoglobulin light chain variable domain (V _L ), wherein the CDR1 ′ has the amino acid sequence Arg-Ala-Ser-Gln-Ser-Ile-Gly-Ser-Ser-Leu-His, The CDR2 'has the amino acid sequence Ala-Ser-Gln-Ser-Phe-Ser and the CDR3' has the amino acid sequence His-Gln-Ser-Ser-Ser-Leu-Pro , domain (V _L );
Binding molecules comprising at least one antigen binding site comprising: as well as their direct equivalents.

In a further aspect, the present invention also provides an IL-1β binding molecule comprising both heavy chain (V _H ) and light chain (V _L ) variable domains, wherein the IL-1β binding molecule is a) hypervariable in order. An immunoglobulin heavy chain variable domain (V _H ) comprising the regions CDR1, CDR2 and CDR3, wherein the CDR1 has the amino acid sequence Ser-Tyr-Trp-Ile-Gly, and the CDR2 has the amino acid sequence Ile-Ile-Tyr -Pro-Ser-Asp-Ser-Asp-Thr-Arg-Tyr-Ser-Pro-Ser-Phe-Gln-Gly, and the CDR3 has the amino acid sequence Tyr-Thr-Asn-Trp-Asp-Ala- Phe-Asp-Ile domain having _(V H), and b) the amino acid sequence His-Gln-Ser-Ser Immunoglobulin light chain variable domain comprising the hypervariable regions CDR3 'having a _{Ser-Leu-Pro (V L} );
Binding molecules comprising at least one antigen binding site comprising: as well as their direct equivalents are provided.

In a further aspect, the invention provides an IL-1β binding molecule comprising both heavy chain (V _H ) and light chain (V _L ) variable domains, the IL-1β binding molecule comprising:
a) an immunoglobulin heavy chain variable domain (V _H ) comprising in turn the hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence Ser-Tyr-Trp-Ile-Gly, wherein the CDR2 is an amino acid The sequence Ile-Ile-Tyr-Pro-Ser-Asp-Ser-Asp-Thr-Arg-Tyr-Ser-Pro-Ser-Phe-Gln-Gly, and the CDR3 has the amino acid sequence Tyr-Thr-Asn- A domain having a Trp-Asp-Ala-Phe-Asp-Ile (V _H ), and b) an immunoglobulin light chain variable domain (V _L ) comprising in turn the hypervariable regions CDR1 ′, CDR2 ′ and CDR3 ′ The CDR1 ′ has the amino acid sequence Arg-Ala-Ser-Gln-Ser-Val-Se. r-Ser-Tyr-Leu-Ala, the CDR2 'has the amino acid sequence Asp-Ala-Ser-Asn-Arg-Ala-Thr, and the CDR3' has the amino acid sequence His-Gln-Ser-Ser. A binding molecule comprising at least one antigen binding site comprising a domain (V _L ) having Ser-Leu-Pro ; as well as its direct equivalents.

Analysis of mRNA obtained from peripheral blood cells demonstrates down-regulation of IL-1b and IL-1b-induced gene transcription within 24 hours of treatment with ACZ885. This suggests that ACZ885 can interrupt the positive feedback loop in vivo that leads to autonomous overproduction of IL-1β in patients. This assertion is also supported by the initial properties of the PZ / PD effect of ACZ885, which shows an interference with IL-1b production following treatment of the patient with ACZ885. This particular ability of ACZ885 can contribute to long-term clinical effects (indicating a causal relationship).

The present invention includes the following aspects.
[1]
Use of an IL-1β compound for the manufacture of a medicament for treating an autoinflammatory syndrome.
[2]
A method for treating an autoinflammatory syndrome in a patient in need of treatment, comprising administering to the patient an effective amount of an IL-1β compound.
[3]
A pharmaceutical composition for use in the treatment of autoinflammatory syndrome comprising an IL-1β compound together with a pharmaceutically acceptable excipient, diluent or carrier.
[4]
An IL- 1β binding molecule comprising an antigen-binding site comprising at least one immunoglobulin heavy chain variable domain (V _H ) wherein the IL-β compound in turn comprises the hypervariable regions CDR1, CDR2 and CDR3 , wherein CDR1 is an amino acid It has the sequence Val-Tyr-Gly-Met-Asn, and the CDR2 has the amino acid sequence Ile-Ile-Trp-Tyr-Asp-Gly-Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys -Gly, and the CDR3 has the amino acid sequence Asp-Leu-Arg-Thr-Gly-Pro; as well as their direct equivalents, [1], [2] or [3] above Or a method or pharmaceutical composition for treatment according to claim 1.
[5]
An IL- 1β binding molecule wherein the IL-β compound comprises both heavy chain (V _H ) and light chain (V _L ) variable domains, wherein the IL-1β binding molecule is
a) an immunoglobulin heavy chain variable domain (V _H ) comprising in turn the hypervariable regions CDR1, CDR2 and CDR3 , said CDR1 having the amino acid sequence Val-Tyr-Gly-Met-Asn, wherein the CDR2 is an amino acid The sequence Ile-Ile-Trp-Tyr-Asp-Gly-Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly and the CDR3 has the amino acid sequence Asp-Leu-Arg- A domain with Thr-Gly-Pro (V _H ), and
b) an immunoglobulin light chain variable domain (V _L ) comprising in turn the hypervariable regions CDR1 ′, CDR2 ′ and CDR3 ′ , the CDR1 ′ comprising the amino acid sequence Arg-Ala-Ser-Gln-Ser-Ile-Gly -Ser-Ser-Leu-His, the CDR2 'has the amino acid sequence Ala-Ser-Gln-Ser-Phe-Ser, and the CDR3' has the amino acid sequence Gln-Gln-Arg-Ser-Asn- Domain (V _L ) with Trp-Met-Phe-Pro ;
A use or treatment method or pharmaceutical composition according to any of [1] to [4] above, which is a binding molecule comprising at least one antigen binding site comprising: and direct equivalents thereof.
[6]
Either the first domain in which the IL-β compound has an amino acid sequence substantially identical to that shown in SEQ ID NO: 1 or the second domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 2 The use or method for treating or a pharmaceutical composition according to any one of [1] to [5] above, which is an IL-1β binding molecule containing at least one antigen-binding site.
[7]
The use, the method for treating or the pharmaceutical composition according to any one of [1] to [6] above, wherein the autoinflammatory syndrome is juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome or Maccle Wells syndrome.
[8]
The use, the method for treating or the pharmaceutical composition according to any one of [1] to [7] above, wherein the IL-β compound is applied once or less a week.
[9]
The use, the method for treating or the pharmaceutical composition according to any one of [1] to [7] above, wherein the application of the IL-β compound is subcutaneous.

Claims (9)

  Use of an IL-1β compound for the manufacture of a medicament for treating an autoinflammatory syndrome. A method for treating an autoinflammatory syndrome in a patient in need of treatment, comprising administering to the patient an effective amount of an IL-1β compound. A pharmaceutical composition for use in the treatment of autoinflammatory syndrome comprising an IL-1β compound together with a pharmaceutically acceptable excipient, diluent or carrier. IL-1β comprising an antigen binding site wherein the IL-β compound comprises at least one immunoglobulin heavy chain variable domain (V _H ) comprising in turn the hypervariable regions CDR1, CDR2 and CDR3
A binding molecule, the CDR1 comprising the amino acid sequence Val-Tyr-Gly-Met-Asn
The CDR2 has the amino acid sequence Ile-Ile-Trp-Tyr-Asp-Gly-
Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-
Gly and the CDR3 has the amino acid sequence Asp-Leu-Arg-Thr-Gl
The use, method for treating or pharmaceutical composition according to claim 1, 2 or 3, which is a binding molecule having y-Pro; and their direct equivalents. IL-1 in which the IL-β compound contains both heavy chain (V _H ) and light chain (V _L ) variable domains
a β-binding molecule, wherein the IL-1β binding molecule is a) an immunoglobulin heavy chain variable domain (V _H ) that in turn comprises the hypervariable regions CDR1, CDR2 and CDR3, the CDR1 comprising the amino acid sequence Val-Tyr -Gly-Met
-Asn, and the CDR2 has the amino acid sequence Ile-Ile-Trp-Tyr-Asp-
Gly-Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-
Lys-Gly and the CDR3 has the amino acid sequence Asp-Leu-Arg-Th
a domain having r-Gly-Pro (V _H ), and b) an immunoglobulin light chain variable domain (V _L ) comprising in turn hypervariable regions CDR1 ′, CDR2 ′ and CDR3 ′, wherein CDR1 ′ is an amino acid Arg-Ala-Ser sequence
-Gln-Ser-Ile-Gly-Ser-Ser-Leu-His
2 ′ has the amino acid sequence Ala-Ser-Gln-Ser-Phe-Ser and the CDR3 ′ has the amino acid sequence Gln-Gln-Arg-Ser-Asn-Trp-Met-
Domain with Phe-Pro (V _L );
The use, method for treating or pharmaceutical composition according to any of claims 1 to 4, which is a binding molecule comprising at least one antigen binding site comprising: and direct equivalents thereof. Either the first domain in which the IL-β compound has an amino acid sequence substantially identical to that shown in SEQ ID NO: 1 or the second domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 2 The use, method for treating or pharmaceutical composition according to any of claims 1 to 5, which is an IL-1β binding molecule comprising at least one antigen binding site. 7. The use, method for treating or pharmaceutical composition according to any of claims 1 to 6, wherein the autoinflammatory syndrome is juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome or Maccle Wells syndrome. 8. The use, method for treatment or pharmaceutical composition according to any of claims 1 to 7, wherein the IL- [beta] compound is applied once a week or less frequently. Use, method for treatment or pharmaceutical composition according to any of claims 1 to 7, wherein the application of the IL-β compound is subcutaneous.